DiffHiChIP: Identifying differential chromatin contacts from HiChIP data.

Chromosome conformation capture (3C) assays such as HiChIP are widely used to study interactions between cis-regulatory and structural elements. However, robust methods for detecting condition-specific loops remain limited. We introduce DiffHiChIP, the first comprehensive framework to call differential loops from HiChIP and similar 3C protocols. DiffHiChIP supports DESeq2 and edgeR using either a complete contact map or a subset of contacts for background estimation, incorporates edgeR with generalized linear model (GLM) using either quasi-likelihood F test or likelihood ratio test, and implements independent hypothesis weighting (IHW) as well as a distance stratification technique for modeling distance decay of contacts in estimating statistical significance. Our results on five datasets suggest that edgeR GLM-based models with IHW correction reliably capture differential interactions, including long-range interactions, that are supported by published Hi-C data and reference studies. As HiChIP data become increasingly used for modeling chromatin regulation, DiffHiChIP promises to have a broad impact and utility.